Although it has become a commonly accepted explanation for the neurobiology of depression among the general public (mostly due to misleading advertisements by pharmaceutical companies), the idea that depression is caused primarily by a serotonin “imbalance” is a description of the processes underlying the disorder so simplified it renders itself inaccurate. The serotonin hypothesis, proposed decades ago, gained increased support of late due to the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treating depression. SSRIs increase extracellular levels of serotonin by blocking its reabsorption from the synaptic cleft back into the cell. The effectiveness of SSRIs led many to draw a one to one correlation between depression and low serotonin levels.

This overactivity of the neuroendocrine system, specifically the hypothalamic-pituitary-adrenal (HPA) axis, can cause the release of cytokines. Cytokines are part of an immune response, but in this case they may end up causing further instability in the neuroendocrine system along with concomitant fatigue, loss of appetite, hypersensitivity to pain, and reduced libido.

Now enter serotonin. Serotonin is a type of neurotransmitter known as a monoamine, as are dopamine and norepinephrine. After they are released into the synaptic cleft, monoamines are quickly broken down by an enzyme called monoamine oxidase A (MAO-A). Then their constituents are taken back up into the neuron and recycled for future use.

MAO-A activity appears to be increased during depression. Thus, monoamines are metabolized more quickly, allowing less of them to reach their receptors on the other side of the synaptic cleft. Lower monoamine levels can negatively affect mood, cognition, motivation, and sensation of pain. It is thought that higher levels of cortisol may increase MAO-A levels, intensifying the symptoms of depression, and providing the explanation for why SSRIs can alleviate them.

Even this is a simplified illustration of the processes of depression, making the “chemical imbalance” described in drug commercials more similar to a children’s book than a thorough explanation. And a full understanding of the process has not yet been reached. An article in this week’s Science leads us closer to that understanding, however, by examining the effects of fluoxetine on neuronal plasticity in the visual cortex of the rat.

The neurogenesis and increases in BDNF caused by antidepressants appear to be as closely, if not more so, correlated with their effectiveness as changes in the neurotransmission of monoamines like serotonin. In order to further elucidate exactly how these processes work, and specifically if they cause beneficial modifications of neuronal circuitry in the brain, the authors of the report in Science investigated whether fluoxetine (Prozac) could cause plastic changes in the visual cortex that would improve vision in an impaired rat's eye.

They found that the neurogenesis promoted by fluoxetine was significant enough to restore vision in the rat's eye if the other eye was covered (covering the strong eye causes the cortex to focus on making improvements to the visual system through modifying the connections for the weaker eye). They had set out to investigate antidepressant-induced brain plasticity and neurogenesis, and in the process found that antidepressants may also be effective in the treatment of amblyopia (often referred to as lazy eye). Additionally, they provided further support for the idea that neurogenesis and the regulation of BDNF is just as important in treating depression as monoamine levels—and probably the more essential factor. The serotonin hypothesis is a useful way for drug companies to easily explain depression, but it seems to be far from the whole truth.

Neuroscientifically Challenged

Neuroscientifically Challenged is a neuroscience learning resource. In addition to a blog that discusses science current events in a non-technical manner, you will also find a number of videos and articles that you can use to learn about basic principles of science and the brain.